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Genomic and neural analysis of the estradiol-synthetic pathway in the zebra finch.

London SE, Clayton DF - BMC Neurosci (2010)

Bottom Line: We found very little qualitative overlap in predicted transcription factor binding sites in the genes for two cholesterol transport proteins, the 18 kDa cholesterol transport protein (TSPO) and steroidogenic acute regulatory protein (StAR).We therefore performed in situ hybridization for TSPO and found that its mRNA was not always detected in brain regions where StAR and steroidogenic enzymes were previously shown to be expressed.Coordinated transcription of multiple steroidogenic genes is possible, but results were inconsistent with the hypothesis that StAR and TSPO mRNAs are co-regulated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. slondon@illinois.edu

ABSTRACT

Background: Steroids are small molecule hormones derived from cholesterol. Steroids affect many tissues, including the brain. In the zebra finch, estrogenic steroids are particularly interesting because they masculinize the neural circuit that controls singing and their synthesis in the brain is modulated by experience. Here, we analyzed the zebra finch genome assembly to assess the content, conservation, and organization of genes that code for components of the estrogen-synthetic pathway and steroid nuclear receptors. Based on these analyses, we also investigated neural expression of a cholesterol transport protein gene in the context of song neurobiology.

Results: We present sequence-based analysis of twenty steroid-related genes using the genome assembly and other resources. Generally, zebra finch genes showed high homology to genes in other species. The diversity of steroidogenic enzymes and receptors may be lower in songbirds than in mammals; we were unable to identify all known mammalian isoforms of the 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase families in the zebra finch genome assembly, and not all splice sites described in mammals were identified in the corresponding zebra finch genes. We did identify two factors, Nobox and NR1H2-RXR, that may be important for coordinated transcription of multiple steroid-related genes. We found very little qualitative overlap in predicted transcription factor binding sites in the genes for two cholesterol transport proteins, the 18 kDa cholesterol transport protein (TSPO) and steroidogenic acute regulatory protein (StAR). We therefore performed in situ hybridization for TSPO and found that its mRNA was not always detected in brain regions where StAR and steroidogenic enzymes were previously shown to be expressed. Also, transcription of TSPO, but not StAR, may be regulated by the experience of hearing song.

Conclusions: The genes required for estradiol synthesis and action are represented in the zebra finch genome assembly, though the complement of steroidogenic genes may be smaller in birds than in mammals. Coordinated transcription of multiple steroidogenic genes is possible, but results were inconsistent with the hypothesis that StAR and TSPO mRNAs are co-regulated. Integration of genomic and neuroanatomical analyses will continue to provide insights into the evolution and function of steroidogenesis in the songbird brain.

Show MeSH
The estradiol-synthetic pathway and nuclear receptors. Cholesterol is the universal steroid substrate. Initiation of steroidogenesis begins with the transport of cholesterol, via the action of the 18 kDa cholesterol transport protein (TSPO) and/or the steroidogenic acute regulatory protein (StAR), to the first enzyme in the pathway, cytochrome P450 side chain cleavage (CYP11A1). From pregnenolone, four more enzymes are required to produce estradiol: 3β-hydroxsteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17), 17β-hydroxysteroid dehydrogenases (HSD17B), and cytochrome P450 aromatase (CYP19). Cholesterol transport proteins and enzymes are in bold italics. Steroids are in plain text. The four major nuclear receptors for the three classes of steroids produced along the estradiol-synthetic pathway are in italicized parentheses: progesterone receptor (PR), estrogen receptor α (ERα), estrogen receptor β (ERβ), and androgen receptor (AR).
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Figure 1: The estradiol-synthetic pathway and nuclear receptors. Cholesterol is the universal steroid substrate. Initiation of steroidogenesis begins with the transport of cholesterol, via the action of the 18 kDa cholesterol transport protein (TSPO) and/or the steroidogenic acute regulatory protein (StAR), to the first enzyme in the pathway, cytochrome P450 side chain cleavage (CYP11A1). From pregnenolone, four more enzymes are required to produce estradiol: 3β-hydroxsteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17), 17β-hydroxysteroid dehydrogenases (HSD17B), and cytochrome P450 aromatase (CYP19). Cholesterol transport proteins and enzymes are in bold italics. Steroids are in plain text. The four major nuclear receptors for the three classes of steroids produced along the estradiol-synthetic pathway are in italicized parentheses: progesterone receptor (PR), estrogen receptor α (ERα), estrogen receptor β (ERβ), and androgen receptor (AR).

Mentions: Steroids are small molecule hormones derived from cholesterol through a series of enzymatic conversions (Figure 1). The first steroidogenic enzyme resides in the inner mitochondrial membrane, and the rate-limiting step of steroidogenesis is the transport of cholesterol across the outer mitochondrial membrane. Two major cholesterol transport proteins, which have been proposed to work in concert as part of a protein complex, are the steroidogenic acute regulatory protein (StAR) and the 18 kDa cholesterol transport protein (TSPO; previously named peripheral type benzodiazepine receptor) [24-29]. Steroid synthesis starts with the action of cytochrome P450 side chain cleavage (CYP11A1), which produces pregnenolone. Pregnenolone can be converted to either progesterone or dehydroepiandrosterone via the action of cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17) or 3β-hydroxsteroid dehydrogenase/Δ5,Δ4 isomerase (HSD3B1), respectively. Androstenedione is produced from progesterone through the activity of HSD3B1 and from dehydroepiandrosterone through the activity of CYP17. Androstenedione can be converted to testosterone or an estrogen, estrone, via the activity of 17β-hydroxysteroid dehydrogenases (HSD17B) or cytochrome P450 aromatase (CYP19), respectively. HSD17B can also convert estrone to estradiol, and CYP19 metabolizes testosterone into estradiol. Of note is the fact that multiple HSD3B and HSD17B types exist in other animals, and that several of HSD17B enzymes can use androgens and estrogens as substrates [30-32].


Genomic and neural analysis of the estradiol-synthetic pathway in the zebra finch.

London SE, Clayton DF - BMC Neurosci (2010)

The estradiol-synthetic pathway and nuclear receptors. Cholesterol is the universal steroid substrate. Initiation of steroidogenesis begins with the transport of cholesterol, via the action of the 18 kDa cholesterol transport protein (TSPO) and/or the steroidogenic acute regulatory protein (StAR), to the first enzyme in the pathway, cytochrome P450 side chain cleavage (CYP11A1). From pregnenolone, four more enzymes are required to produce estradiol: 3β-hydroxsteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17), 17β-hydroxysteroid dehydrogenases (HSD17B), and cytochrome P450 aromatase (CYP19). Cholesterol transport proteins and enzymes are in bold italics. Steroids are in plain text. The four major nuclear receptors for the three classes of steroids produced along the estradiol-synthetic pathway are in italicized parentheses: progesterone receptor (PR), estrogen receptor α (ERα), estrogen receptor β (ERβ), and androgen receptor (AR).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865489&req=5

Figure 1: The estradiol-synthetic pathway and nuclear receptors. Cholesterol is the universal steroid substrate. Initiation of steroidogenesis begins with the transport of cholesterol, via the action of the 18 kDa cholesterol transport protein (TSPO) and/or the steroidogenic acute regulatory protein (StAR), to the first enzyme in the pathway, cytochrome P450 side chain cleavage (CYP11A1). From pregnenolone, four more enzymes are required to produce estradiol: 3β-hydroxsteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17), 17β-hydroxysteroid dehydrogenases (HSD17B), and cytochrome P450 aromatase (CYP19). Cholesterol transport proteins and enzymes are in bold italics. Steroids are in plain text. The four major nuclear receptors for the three classes of steroids produced along the estradiol-synthetic pathway are in italicized parentheses: progesterone receptor (PR), estrogen receptor α (ERα), estrogen receptor β (ERβ), and androgen receptor (AR).
Mentions: Steroids are small molecule hormones derived from cholesterol through a series of enzymatic conversions (Figure 1). The first steroidogenic enzyme resides in the inner mitochondrial membrane, and the rate-limiting step of steroidogenesis is the transport of cholesterol across the outer mitochondrial membrane. Two major cholesterol transport proteins, which have been proposed to work in concert as part of a protein complex, are the steroidogenic acute regulatory protein (StAR) and the 18 kDa cholesterol transport protein (TSPO; previously named peripheral type benzodiazepine receptor) [24-29]. Steroid synthesis starts with the action of cytochrome P450 side chain cleavage (CYP11A1), which produces pregnenolone. Pregnenolone can be converted to either progesterone or dehydroepiandrosterone via the action of cytochrome P450 17α-hydroxylase/17,20 lyase (CYP17) or 3β-hydroxsteroid dehydrogenase/Δ5,Δ4 isomerase (HSD3B1), respectively. Androstenedione is produced from progesterone through the activity of HSD3B1 and from dehydroepiandrosterone through the activity of CYP17. Androstenedione can be converted to testosterone or an estrogen, estrone, via the activity of 17β-hydroxysteroid dehydrogenases (HSD17B) or cytochrome P450 aromatase (CYP19), respectively. HSD17B can also convert estrone to estradiol, and CYP19 metabolizes testosterone into estradiol. Of note is the fact that multiple HSD3B and HSD17B types exist in other animals, and that several of HSD17B enzymes can use androgens and estrogens as substrates [30-32].

Bottom Line: We found very little qualitative overlap in predicted transcription factor binding sites in the genes for two cholesterol transport proteins, the 18 kDa cholesterol transport protein (TSPO) and steroidogenic acute regulatory protein (StAR).We therefore performed in situ hybridization for TSPO and found that its mRNA was not always detected in brain regions where StAR and steroidogenic enzymes were previously shown to be expressed.Coordinated transcription of multiple steroidogenic genes is possible, but results were inconsistent with the hypothesis that StAR and TSPO mRNAs are co-regulated.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. slondon@illinois.edu

ABSTRACT

Background: Steroids are small molecule hormones derived from cholesterol. Steroids affect many tissues, including the brain. In the zebra finch, estrogenic steroids are particularly interesting because they masculinize the neural circuit that controls singing and their synthesis in the brain is modulated by experience. Here, we analyzed the zebra finch genome assembly to assess the content, conservation, and organization of genes that code for components of the estrogen-synthetic pathway and steroid nuclear receptors. Based on these analyses, we also investigated neural expression of a cholesterol transport protein gene in the context of song neurobiology.

Results: We present sequence-based analysis of twenty steroid-related genes using the genome assembly and other resources. Generally, zebra finch genes showed high homology to genes in other species. The diversity of steroidogenic enzymes and receptors may be lower in songbirds than in mammals; we were unable to identify all known mammalian isoforms of the 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase families in the zebra finch genome assembly, and not all splice sites described in mammals were identified in the corresponding zebra finch genes. We did identify two factors, Nobox and NR1H2-RXR, that may be important for coordinated transcription of multiple steroid-related genes. We found very little qualitative overlap in predicted transcription factor binding sites in the genes for two cholesterol transport proteins, the 18 kDa cholesterol transport protein (TSPO) and steroidogenic acute regulatory protein (StAR). We therefore performed in situ hybridization for TSPO and found that its mRNA was not always detected in brain regions where StAR and steroidogenic enzymes were previously shown to be expressed. Also, transcription of TSPO, but not StAR, may be regulated by the experience of hearing song.

Conclusions: The genes required for estradiol synthesis and action are represented in the zebra finch genome assembly, though the complement of steroidogenic genes may be smaller in birds than in mammals. Coordinated transcription of multiple steroidogenic genes is possible, but results were inconsistent with the hypothesis that StAR and TSPO mRNAs are co-regulated. Integration of genomic and neuroanatomical analyses will continue to provide insights into the evolution and function of steroidogenesis in the songbird brain.

Show MeSH